The long term goal of the proposed research is to develop effective treatment for spinobulbar muscular atrophy (SBMA), a neurodegenerative disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). My laboratory has recently published compelling evidence that native functions of the androgen receptor are essential mediators of toxicity. Specifically, we used a combination of Drosophila genetics and functional genomics to learn that interaction of the AF-2 domain of AR with nuclear hormone co-regulatory protein is an essential step in pathogenesis. This exciting finding suggests that modulation of native AR function with existing anti-androgen therapies may be effective in the treatment of this devastating neurodegenerative disease. The critical next steps are corroboration of this mechanism of pathogenesis in a mammalian model of SBMA and further elucidation of the specific AR functions that are perturbed by polyglutamine expansion, as outlined in the accompanying proposal. A related question is determination of the most important component of the motor unit to be targeted in therapy: motor neuron or muscle. Toward that end we have initiated experiments to address three specific aims. First, we have generated a novel series of transgenic mice that conditionally express wild type or mutant forms of human androgen receptor to corroborate these findings in a mammalian model. Second, we will pursue proteomic approaches to characterize how polyglutamine expansion influences native interactions of the androgen receptor. Third, we will engineer conditional expression exclusively in motor neuron or muscle to gauge the relative contributions of these tissues to the degenerative phenotype in SBMA mice.